B Cells and T Follicular Helper Cells Mediate Response to Checkpoint Inhibitors in High Mutation Burden Mouse Models of Breast Cancer

Cell. 2019 Nov 14;179(5):1191-1206.e21. doi: 10.1016/j.cell.2019.10.028.


This study identifies mechanisms mediating responses to immune checkpoint inhibitors using mouse models of triple-negative breast cancer. By creating new mammary tumor models, we find that tumor mutation burden and specific immune cells are associated with response. Further, we developed a rich resource of single-cell RNA-seq and bulk mRNA-seq data of immunotherapy-treated and non-treated tumors from sensitive and resistant murine models. Using this, we uncover that immune checkpoint therapy induces T follicular helper cell activation of B cells to facilitate the anti-tumor response in these models. We also show that B cell activation of T cells and the generation of antibody are key to immunotherapy response and propose a new biomarker for immune checkpoint therapy. In total, this work presents resources of new preclinical models of breast cancer with large mRNA-seq and single-cell RNA-seq datasets annotated for sensitivity to therapy and uncovers new components of response to immune checkpoint inhibitors.

Keywords: B cells; CTLA4; PD1; T cells; TMB; breast cancer; genomics; immune checkpoints; immunotherapy; mouse models; tumor mutation burden.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology*
  • CTLA-4 Antigen / metabolism
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genetic Engineering
  • Genome
  • Humans
  • Immunoglobulin G / metabolism
  • Immunotherapy*
  • Lymphocyte Activation / immunology
  • Mammary Neoplasms, Animal / genetics*
  • Mammary Neoplasms, Animal / immunology*
  • Mammary Neoplasms, Animal / therapy
  • Mutation / genetics*
  • Receptors, Antigen, B-Cell / metabolism
  • Receptors, Antigen, T-Cell / metabolism
  • T-Lymphocytes, Helper-Inducer / immunology*
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / immunology
  • Triple Negative Breast Neoplasms / pathology
  • Triple Negative Breast Neoplasms / therapy


  • CTLA-4 Antigen
  • Immunoglobulin G
  • Receptors, Antigen, B-Cell
  • Receptors, Antigen, T-Cell